Volume 19, Issue 1, Pages (January 2011)

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Volume 19, Issue 1, Pages 37-44 (January 2011) Helix 11 Dynamics Is Critical for Constitutive Androstane Receptor Activity Edward Wright, Scott A. Busby, Sarah Wisecarver, Jeremy Vincent, Patrick R. Griffin, Elias J. Fernandez Structure Volume 19, Issue 1, Pages 37-44 (January 2011) DOI: 10.1016/j.str.2010.11.008 Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 1 Comparison of the Two CAR Ligands Used in This Study (A) The chemical structures of CAR and TCPOBOP are shown. (B) TCPOBOP is a more potent agonist in cell-based reporter gene assays using the βRE response element. The data is shown in relative luciferase units (RLU). (C) TCPOBOP promotes higher affinity for coactivator than meclizine in ITC experiments. Structure 2011 19, 37-44DOI: (10.1016/j.str.2010.11.008) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 2 TCPOBOP Binding to CAR Results in a Conformational Change in RXR (A) Change in intrinsic tryptophan fluorescence of RXR is monitored in response to increasing levels of CAR ligand. (B) TCPOBOP elicits a dose-responsive change in RXR fluorescence while meclizine does not. See also Figures S1 and S2. Structure 2011 19, 37-44DOI: (10.1016/j.str.2010.11.008) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 3 Perturbations in HDX Data for CAR and RXR LBDs Cartoon rendition of percent reduction in HDX of ligand bound CAR:RXR heterodimer complex relative to unliganded receptor. Increasing protections from deuterium exchange are represented as color gradient from light to dark blue as shown. TCPOBOP is shown as an orange space-filled model. (A) CAR portion of CAR(TCPOBOP):RXR (76 peptides). (B) RXR portion of CAR(TCPOBOP):RXR (84 peptides). (C) CAR portion of the CAR(meclizine):RXR (76 peptides). (D) Residues within the encircled region in the unliganded CAR LBD model are mutated and tested for activity. See also Figure S3. Structure 2011 19, 37-44DOI: (10.1016/j.str.2010.11.008) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 4 Transactivation and Coactivator Binding Assays of CAR:RXR (A) b) Luciferase reporter assay showing ligand (TCPOBOP) mediated CAR:RXR transactivation of the LXRE-TK-Luc reporter plasmid in CV-1 cells. Results are reported in relative luciferase units (RLU). (B and C) (B) Binding isotherms from titrations of SRC1 peptide into unliganded (L343A)CAR:RXR and (L343F)CAR:RXR and (C) summary of the SRC1 binding assay. Structure 2011 19, 37-44DOI: (10.1016/j.str.2010.11.008) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 5 Comparison of CAR LBD Structures (A) Structure of the CAR(androstenol) complex (REF). (B) Proposed model for the structure of unliganded CAR based on the HDX data and site-directed mutagenesis studies for residues 338–343. (C) Structure of the CAR(TCPOBOP) complex (REF). The circled regions have different conformations in the CAR(androstenol) and CAR(TCPOBOP) structures. Ligands are shown in mesh format. Structure 2011 19, 37-44DOI: (10.1016/j.str.2010.11.008) Copyright © 2011 Elsevier Ltd Terms and Conditions